Acylated and alkylated derivatives of 2-aminohexahydrobenzo(a)quinolizines

ABSTRACT

ACYLATED AND ALKYLATED DERIVATIVES OF 2-AMINOHEXAHYDROBENZO(A)QUINOLIZINE AND PHARMACOLOGICALLY ACCEPTABLE SALTS THEREOF THAT ARE USEFUL AS ANTIHYPERTENSIVE AGENTS. PREPARED BY REACTING 2-OXO-1,3,4,6,7,11B-HEXAHYDRO-2HBENZO(A)QUINOLIZINE WITH AN AMINE TO FORM A SCHIFF BASE WHICH IS THEN REDUCED. THE AMINE IS ACYLATED OR ALKYLATED WITH A HALIDE OR AN ANHYDRIDE.

United States Patent 3,634,431 ACYLATED AND ALKYLATED DERIVATIVES OFZ-AMINOHEXAHYDROBENZO[a]QUINOLIZlNES John William Van Dyke, Jr.,Elkhart, Ind., assignor to Miles Laboratories, Inc., Elkhart, Ind.

N 0 Drawing. Continuation-impart of application Ser. No.

858,850, Sept. 17, 1969, which is a division of application Ser. No.650,579, July 3, 1967. This-application Dec. 22, 1969, Ser. No. 887,344

Int. Cl. C07d 35/38 US. Cl. 260-287 R 18 Claims ABSTRACT OF THEDISCLOSURE Acylated and alkylated derivatives of2-aminohexahydrobenzo[a] quinolizine and pharmacologically acceptablesalts thereof that are useful as antihypertensive agents. Prepared byreacting 2-oxo-1,3,4,6,7,1lb-hexahydro-ZH- benzo[a]quinolizine with anamine to form a Schiff base which is then reduced. The amine is acylatedor alkylated with a halide or an anhydride.

This application is a continuation-in-part of my copending applicationSer. No. 858,850 filed Sept. 17, 1969 which is a division of mycopending application Ser. No. 650,579 filed July 3, 1967 both nowabandoned.

This invention relates to new and useful compositions of matter and moreparticularly to acylated and alkylated derivatives of2-aminohexahydrobenzo[a]quinolizine and a novel process for thepreparation of such compounds.

Compounds of the invention may be represented by the structural formula:

wherein R is a member selected from the group consisting of H, OH andlower alkoxy, R is a member selected from the group consisting of H, OHand lower =alkoxy, R is a member selected from the group consisting ofH, (lower) alkyl, cycloalkyl of between 3 and 7 carbon atoms, phenyl,substituted phenyl, diphenyl, phenyl(lower) alkyl and substitutedphenyl(lower)alkyl in which the substituents are members selected fromthe group consisting of halogen, (lower)alkyl, lower alkoxy, cyano,lower alkoxy carbonyl and nitro, R is a member selected from the groupconsisting of and R is a member selected from the group consisting of H,(lower)alkyl and phenyl, and pharmacologically acceptable salts thereof.Preferably the (lower)alkyl groups in compounds of this invention willhave between 1 and 4 carbon atoms.

3,634,431 Patented Jan. 11, 1972 The compounds of this invention may beprepared according to the following reaction sequence:

PtOz/H or NaBH4 in which the values for R, R R R and R correspondrespectively with their previous descriptions and X is a halogen.

In the reaction sequence,2-oxo-1,3,4,6,7,1lb-hexahydro-2H-benzo[a]quinolizine is reacted with anamine in a suitable solvent to form a Schitf base. The solvent utilizedis not critical and may be dry toluene, benzene, xylene, etc. Thereaction mixture is advantageously maintained under reflux in thepresence of a catalyst. The reaction time is not critical andadvantageously is dependent upon the required amount of water beingcollected and may be between about one and twelve or more hours. Thecatalyst may be an acid catalyst and is preferably an organic acidcatalyst such as p-toluenesulfonic acid.

The Schitf base that is formed is then reduced, forming an amine.Advantageously, this reduction is carried out in a suitable solvent suchas methanol, ethanol, or 2-propa- 1101. To form the trans isomers, thereduction is beneficially carried out using NaBH Preferably, forcatalytic hydrogenation PtO; is used as a catalyst.

The amine is then subjected to an acylation or alkylation with a halideor anhydride having the desired R radical. Although the operatingconditions are not critical, this step is preferably performed underreflux for between about one and six hours. The resulting compound maythen be purified according to known practices.

2-oxo-1,3,4,6,7,1 lb-hexahydro-ZH-benzo [a] quinolizine, the startingmaterial in the above reaction sequence may be prepared by the followingreaction sequence:

The novel compounds, either in the form of the free bases or acceptableaddition salts, are useful as antihypertensive agents.

Medications prepared with these compounds as active ingredients arereadily formulated by mixing the compounds in dosage units with fillers,carriers, extenders and/ or excipients generally used in preparingpharmaceutical formulations. When mixed in such a formulation, thecompound may be in the form of a free base and is preferably in the formof a pharmacologically acceptable addition salt. The medication may beeither in solid or liquid form and may be compounded as tablets,powders, capsules, suspensions and similar dosage forms according toaccepted manufacturing methods. These medications may be administered,for example, orally or subcutaneously, in conformity with recognizedpharmacological techniques.

The invention will be further understood by referring to the followingexamples which illustrate the preparation of compounds according to theinvention. These examples will make clear to those skilled in the arthow to facilely prepare other compounds within the scope of thisinvention as set forth in the appended claims.

EXAMPLE 1 N- [2- 1,3 ,4,6,7,1 lb-hexahydro-ZH-benzo [a] quinolizinyl)]propionanilide.

Cis and trans isomers.A mixture of 2-oxo-1,3,4,6,7, 11b hexahydro 2Hbenzo[a]quinolizine (5.6 g., 0.027 mole), aniline (2.5 g., 0.027 mole)and 50ml. of dry toluene was refluxed for 12 hours using a Dean-Starktrap with p-toluenesulfonic acid as a catalyst. The solvent was removedin vacuo and the residue extracted with nhexane. The n-hexane solutionwas then concentrated in vacuo and the residue recrystallized fromether. A light tan product crystallized out ('Schifl Base). Yield, 2.14g., M.P. 129-131 C. A solution of the product,2-phenylimino-1,3,4,6,7,1lb-hexahydro 2H benzo[a] quinolizine (2.14 g.,0.007 mole) in dry ethanol was hydrogenated using PtO as a catalyst.After the reaction was complete, about one hour, the catalyst wasremoved by filtration and the filtrate concentrated in vacuo to ,yield2.2 g. of 2-anilino-1,3,4,6,7,1lb-hexahydro 2H benzo[a]quinolizineeThisprocedure was repeated with suflicient quantities of reactants toprovide 20.6 g. of product. A solution of the anilino compound (20.6 g.)in 100 ml. of propionic anhydride was refluxed for about one hour. Theexcesspropionic anhydride was removed in vacuo. The residue wasdissolved in H and made basic with K CO The organic material wasextracted out with CHCl The CHCl was dried, filtered and concentrated invacuo. The residue was taken up in hot ether, filtered and cooled. Whitechunky crystals were obtained and collected by filtration. Yield, 10.05g., M.P. 125-26 C.

Analysis.Calcd. for C H N O (percent): N (basic), 4.19; C, 79.01; H,7.84. Found (percent): N (basic), 4.21; C, 79.12; H, 7.90.

EXAMPLE 2 Trans isomer.The process of this example was the same asExample 1 except as follows:

Larger quantities of reactants were utilized, i.e. 2-oxo-1,3,4,6,7,11b-hexahydro 2H benzo[a]quinolizine (69.5 g., 0.368 mole),aniline (34.2 g., 0.368 mole), and 200 ml. propionic anhydride, and theacylation reflux time was increased to six hours.

Following the acylation, the reaction mixture was evaporated to drynesson a steam bath in vacuo. Water was added to the semi-solid residue andwarmed on a steam bath. The insoluble portion was removed by filtration.The filtrate was put aside. The insoluble portion was dissolved indilute HCl and precipitated with K CO The precipitate was dissolved inCHCI dried over MgSO and the solvent stripped in vacuo. The residue wasslurried with ether, filtered and washed wtih cold ether. A

solid, 29 g., was obtained. The solid was recrystallized twice frombenzene-n-hexane. Yield, 20 g., M.P. 125126 C. The product (15 g.) wasch-romatographed on an alumina column (350 g.). The column was elutedwith benzene and benzene-ether (4:1) to obtain 7.5 g. of the transisomer. The trans isomer was recrystallized from ether. Yield, 7 g.,M.P. 125-126" C.

Analysis.Calcd. for C H N O (percent): C, 79.01; H, 7.84; N, 8.38. Found(percent): C, 78.91; H, 7.96; N, 8.44;

01-1013 max.

1645, 2755 and 2815 cm.

EXAMPLE 3 Analysis.-Calcd. for C H N O (percent): C, 79.01; H, 7.84; N(basic), 4.19; N (total), 8.38. Found (percent): C, 79.35; H, 7.98; N(basic), 4.20; N (total), 8.38.

1645 cm,- (no bands at 2755 or 2815 crnr EXAMPLE 4 N phenyl N(1,3,4,6,7,11b hexahydro-2H-benzo[a]- quinolizine-Z-yl)butyramidemonohydrochloride monomethanolate A Schiff base (73 g.), prepared as inExample 1 was placed in a 3-necked flask equipped with a refluxcondenser and stirrer. Methanol (1500 ml.) was added and stirred duringthe addition of NaBH (19.7 g.). The solution was refluxed for 1 hour andcooled. Water (1500 ml.)

was added to the solution and the methanol removed in vacuo. The aqueoussolution was extracted with ether and dried over MgSO The ether wasremoved in vacuo and the residue recrystallized from absolute ethanol toyield 2 anilino 1,3,4,6,7,1lb-hexahydro-ZH-benzo[a]quinolizine. Asolution of 2-anilino-1,3,4,6,7,1lb-hexahydro-ZI-I- benzo[a]quinolizine(13.9 g.; 0.05 M) and butyric anhydride (15.8 g.; 0.1 M) in ml. ofbenzene was refluxed for 12 hours. The solvent was removed in vacuo andthe resulting yellow oil stirred with hot H O as concentrated HCl wasadded to eflect dissolution. The hot solution was rendered alkaline with20% NaOH. The mixture was extracted with CHC1 The combined CHCl extractswere dried over MgSO and filtered. The solvent was removed in vacuo andthe resulting oil was crystallized and recrystallized from a mixture ofbenzene and n-heptane. The solid was dissolved in a mixture of2-propanol, MeOH, and CHCl To the resulting solution was added 15 ml. of2.7 N HCl in 2-propanol. The solution was concentrated by boiling andEtOAc added. Upon cooling a white solid formed which was recrystallizedfrom a mixture of MeOH and EtOAc. Yield 14.8 g., M.P. 163-168" C.

Analysis.-Calcd. for C H N O Cl (percent): N, 6.72; C,'69.13; H, 7.98.Found (percent): N, 6.61; C, 68.89; H, 8.01.

EXAMPLE 5 N phenyl N (1,3,4,6,7,11b hexahydro-2H-benzo[a]-quinolizine-Z-yl)acetamide hydrochloride A solution of2-anilino-l,3,4,6,7,1lb-hexahydro-ZH- benzo[a]quinolizine (13.9 g.; 0.05M) and acetic anhydride (10.2 g.; 0.1 M) in 100 ml. of benzene wasrefluxed for 12 hours. The solvent was removed in vacuo and theresulting dark oil stirred in hot H O as concentrated HC] was added toeffect dissolution. The hot solution was rendered alkaline with 20% NaOHand cooled. The mixture was extracted with Et O and the combined Et Oextracts were dried over MgSO, and filtered. The solvent was removed invacuo from the filtrate. The resulting oil was crystallized andrecrystallized from a mixture of benzene and n-heptane. Yield 10.4 g.,M.P. 125-127 C. The solid was dissolved in a mixture of 2-propanol andMeOH. To the resulting solution was added 12 ml. of 2.7 N HCl in'2-propanol. The solution was concentrated by boiling and EtOAc was addeduntil crystals began to form. Upon cooling a white crystalline solidformed and was removed by filtration. Yield 10.3 g., M.P. 253259 C.

Analysis.'Calcd. for C H N OCl (percent): N, 7.85; C, 70.67; H, 7.06.Found (percent): N, 7.95; C, 70.27; H, 7.04.

EXAMPLE 6 N phenyl N (1,3,4,6,7,l1b-hexahydro-9,10-dimethoxy- 2H benzo[a]quinolizine 2 yl)propionamide hydrochloride A mixture of9,10-dimethoxy-1,3,4,6,7,1lb-hexahydro- 2H-benzo[a]quinolizine-2-one (55g.; 0.21 M), aniline (21.4 g.; 0.25 M), a catalytic amount ofp-toluenesulfonic acid and 1,000 ml. of toluene was refluxed under anitrogen atmosphere whereupon a clear solution resulted. The solutionwas refluxed for 24 hours utilizing a Dean-Stark trap to remove 4 ml. ofH 0. The solvent was removed in vacuo.-The resulting dark red-orange oilwas dissolved in 1,000 ml. of MeOH and cooled in an ice-bath. SolidNaBH, (20 g.) was added portionwise with stirring and the resultingsolution was left to warm up to room temperature overnight. The solventwas removed in vacuo. The residue was dissolved in hot aqueous HCl andrendered alkaline with 20% NaOI-I. The resulting mixture was extractedwith Et O. The combined -Et O- extracts were dried over MgSO andfiltered. The solvent was removed in vacuo from the filtrate and theresulting dark syrup (70.1 g.) dissolved in 500 ml. of benzene.Propionic anhydride (27.3 g.; 0.21 M) was added and the resultingsolution refluxed for 24 hours. The solvent was removed in vacuo. Theoily residue was dissolved in 500 ml. of hot aqueous HCl and renderedalkaline, while hot, with K CO The resulting mixture was cooled andextracted with Et O. The combined Et O extracts were dried over MgSO,and filtered. The solvent was removed in vacuo from the filtrate toyield a semi-solid residue. The residue was dissolved in hot EtOAc andfiltered twice through charcoal. The resulting clear filtrate (500 ml.)was warmed and 1,000 ml. of petroleum ether added. The solution wasevaporated with gentle heating utilizing a stream of air until thevolume was 500 ml., then 3,500 ml. of petroleum ether was added and theresulting solution allowed to cool slowly. A white solid formed whichwas removed by filtration. Yield 20.5 g., M.P. 173174.5 C.

Analysis.Calcd. for C H N O (percent): N, 7.10; C, 73.07; H, 7.67. Found(percent): N, 6.86; C, 73.19; H, 7.84.

A sample of the above white solid (18.8 g.; 0.04765 M) was stirred inWarm anhydrous Et O (3,760-ml.) and 1,000 ml. of 2-propanol was added.To the resulting solution was added 184 ml. of 2.7 N HCl in 2-propanol.The resulting solution was allowed to cool to room temperature andanhydrous Et O was added until the solution became cloudy. The totalvolume at this point was approximately 16,000 ml. The resulting mixturewas allowed to set for 24 hours at room temperature and for anadditional 24 hours in the refrigerator. The resulting white solid wasremoved by filtration and washed with anhydrous Et O. Yield 16.7 g.,M.P. 247-249 C. dec.

Analysis.Calcd. for C H N O Cl (percent): N, 6.50; C, 66.88; H, 7.25.Found (percent): N, 6.58; C, 66.29; H, 7.19. a

EXAMPLE 7 N phenyl N (1,3,4,6,7,1l b hexahydro 2H benzo [a]quinolizine 2yl) cyclopropane carboxamide monohydrochloride monomethanolateCyclopropane carboxylic acid chloride (8 ml.) was added dropwise to astirred, refluxing solution of 2-anilino- 1,3,4,6,7,11b-hexahydro 2Hbenzo[a]quinolizine (13.9 g.; 0.05 M), ml. of dry THF and 25 ml. of drypyridine. The resulting White mixture was refluxed for 12 hours and thenpoured over ice. The resulting mixture was rendered alkaline with 20%NaOH and diluted with H O to 2 l. A white solid formed which was removedby filtration. The solid was dissolved in a hot mixture of MeOH (100ml.) and CHCl ml.). The solution was cooled and 25 ml. of 2.7 N HCl in2-propanol added. The resulting solution was boiled as MeOH was added.EtOAc was added to the concentrated MeOH solution and the resultingsolution was left to cool. A white solid formed which was removed byfiltration. Yield 19.6 g. melted slowly above 194 C.

Analysis.Calcd. for C H N O Cl (percent): N, 6.75; C, 69.46; H, 7.53.Found (percent): N, 6.69; C, 69.96; H, 7.32.

EXAMPLE 8 N phenyl N (1,3,4,6,7,11b hexahydro 2H benzo [a] quinolizine 2yl)-benzoamide monohydrochloride monomethanolate.

Benzoyl chloride (7 ml.) was added dropwise to a stirred refluxingsolution of 2-anilino-1,3,4,6,7,1lb-hexahydro-2H-|benzo[a]quinolizine(13.9 g., 0.05 M), 100 ml. of dry THF, and 25 ml. of dry pyridine. Theresulting solution was refluxed for 12 hours. The reaction solution waspoured over ice. A white solid formed. 20% NaOH was added to decomposeany excess benzoyl chloride. The mixture was extracted with Et O. Thecombined Et O extracts were dried over MgSO, and filtered. The solventwas removed in vacuo from the filtrate. The resulting oil wascrystallized and recrystallized from a mixture of benzene and n-heptaneto yield a white solid. The solid was dissolved in warm MeOH and 11 ml.of 2.7 N HCl in 2-propanol added. On heating the solution, a solidformed which was removed by filtration and recrystallized from a mixtureof MeOH and EtOAc. Yield 10.3 g., slowly melted above C.

Analysis.Calcd. .for C H N O Cl (percent): N, 6.21; C, 71.91; H, 6.93.Found (percent): N, 6.25; C, 71.67; H, 6.85.

EXAMPLE 9 N cyclohexyl N (1,3,4,6,7,11b hexahydro 2H- benzo[a]quinolizine 2 yl)propionamide hydrochloride (A) 1,3,4,6,7,11b hexahydro2 cyclohexylamino- 2H-benzo[a]quinolizine.--A solution of1,3,4,6,7,11bhexahydro-2H-benzo[a] quinolizine 2 one (20.1 g.; 0.1 M),cyclohexylamine (9.9 g.; 0.1 M), and a catalytic amount ofp-toluenesulfonic acid in 200 m1. of benzene was refluxed for threehours using a Dean-Stark trap to remove the theoretical amount of H 0.The solution was cooled and the solvent removed in vacuo to yield a darkorange oil. The I.-R. spectrum of the oil showed strong imine absorptionat 1660 cmr The oil was dissolved in 200 ml. of MeOH. To this, stirred,ice-cold solution was added, portionwise, NaBH (8.0 g.). After bubblinghad ceased, the solution was refluxed for 1 /2 hours and cooled. Thesolvent was removed in vacuo and the residual oil shaken with a 50:50mixture of H 0 and Et O (400 ml.). The resulting two phases wereseparated and the aqueous phase extracted with Et O. The combinedethereal extracts were dried over MgSO then filtered. The filtrate wasreduced in vacuo to an oil which crystallized upon cooling. An I.R.spectrum of the solid did not show any imine or ketone absorption. Theoil was then distilled to give a yellow oil. Nitrogen analysis of theoil confirmed the free base. Upon standing, the yellow oil solidified toa waxy solid which darkened in color upon standing.

(B) N cyclohexyl N (1,3,4,6,7,11'b hexahydro- 2H benzo[a]quinolizine 2yl)propionamide hydrochloride.l,3,4,6,7,1lb-hexahydro 2 cyclohexylamino-2H-benzo[a]quinolizine (8.0 g.; 0.028 M), Prepared as described in A,was dissolved in 200 ml. of benzene and propionic anhydride (3.6 g.;0.028) was added. The resulting solution was refluxed for 3 hours andcooled to room temperature. The benzene solution was extracted withaqueous Na CO solution, dried over MgSO and filtered. The filtrate wasfiltered while hot through charcoal and diatomaceous earth and thesolvent removed in vacuo to yield a dark orange oil. The IR. spectrumshowed strong amide adsorption at 1630 cm. The oil was dissolved in 100ml. of 2-propanol and 14 ml. of 2.06 N HCl in 2-propanol was added withstirring. Anhydrous Et O was added to the 2-propanol solution until nofurther precipitate was formed. The white. precipitate was removed byfiltration and recrystallized from methanol. Yield 3.3 g., M.P. 2l6225C. dec.

Analysis.-Calcd. for C H N OCl (percent): N(Dumas) 7.43; C, 70.09; H,8.82. Found (percent): N(Dumas) 7.22; C, 69.67; H, 8.99.

EXAMPLE 10 N benzyl N (1,3,4,6,7,11b hexahydro 2H benzo [a]quinolizine-Z-yl) -propionamide hydrochloride (A) 2 benzylamino1,3,4,6,7,11b hexahydro-ZH- benzo[a] quinolizine.1,3,4,6,7,11b hexahydro2H- benzo[a]quinolizine-Z-one (40.25 g.; 0.2 M) was dissolved in 450 ml.dry benzene. Benzylamine (21.43 g.; '0.2 M) was added along with acatalytic amount of p-toluenesulfonic acid and the solution was refluxedfor 3 hours using a Dean-Stark trap to remove 3.6 ml. H O. The

solution was cooled and reduced in vacuo to a syrup. The IR. spectrumshowed the desired imine absorption at 1670 cmf The syrup was dissolvedin 200 ml. of MeOH and cooled in an ice bath. Solid NaBH (16 g.) wasadded in small portions, with stirring, to the cold MeOH solution. Afterbubbling had ceased, the resulting solution was refluxed for one hour,cooled and reduced in vacuo to a volume of 200 ml. Water (33 ml.) wasslowly added followed by the addition of 300 ml. Et O. The resulting twophase system was transferred to a separatory funnel and the aqueouslayer extracted with Et O. The combined Et O extracts were dried overMgSO' and filtered. The filtrate was reduced in vacuo to a syrup. TheI.R. spectrum did not show an imine or ketone absorption.

(B) N benzyl-N-(l,3,4,6,7,1lb-hexahydro-ZH-benzo [a]quino1izine 2yl)propionamide hydrochloride.Benzylamino-1,3,4,6,7,llb hexahydro 2Hbenzo[a]quinolizine (10 g.), .prepared as described in (A), was dis.-solved in 150 ml. of benzene. To the resulting solution was addedpropionic anhydride (4.5 g.; 0.035 M). An initial rise in temperature ofC. was noted. The solution was refluxed for 2 hours, cooled andextracted with aqueous Na CO solution. The benzene layer was dried overMgSO and filtered. The filtrate was reduced in vacuo to a syrup. The LR.spectrum of the syrup showed strong amide absorption atv 1630 cmf Thehydrochloride salt was formed by dissolution of the syrup in Et Ofollowed by bubbling gaseous HCl through the solution. A white solidformed which was removed by filtration and recrystallization fromanhydrous EtOH/EtOAc. Yield 5.7 g., M.P. 194-196 C.

Analysis.Calcd. for C H N OCl (percent): N(Dumas) 7.28; C, 71.76; H,7.59. Found (percent): N(Dumas) 7.13; C, 71.44; H, 7.79.

8 EXAMPLE 11 N-phenethyl-N- [2-( 1,3,4,6,7,l lb-hexahydro-2H-benzo- [a]quinolizine-Z-yl) propionamide hydrochloride sired imine absorption at1670 crnr The syrup was then dissolved in 300 ml. of MeOH and cooled inan ice bath. A solution of NaBH (16 g.) in 15 ml. of MeOH was thenslowly added, with stirring, to the cooled solution of the syrup inMeOH. After bubbling had ceased, the solution was refluxed for 45minutes, cooled and reduced in vacuo to a volume of ml. Water (200 ml.)was slowly added followed by the addition of 200 ml. Et O. The two phasesystem was then transferred to a separatory funnel and the aqueous layerextracted with Et O. The combined Et O extracts Were dried over MgSOthen filtered. The filtrate was reduced in vacuo to a syrup. The I.R.spectrum of the syrup did not show any imine or ketone absorption.

(B) N-phenethyl N [2-(1,3,4,6,7,1lb-hexahydro-ZH- benzo [a]quinolizine-Z-yl) ]propionamide hydrochloride.-

1,3,4,6,7,11b-hexahydro 2-phe'nethylamino-2H-benzo[a] quinolizine (10g.; 0.032 mole), prepared as described in (A), was dissolved in ml.benzene. To the resulting solution was added propionic anhydride (4.5g.; 0.035 mole). An initial rise in temperature of 12 C. was noted. Thesolution was refluxed for 12 hours, cooled and extracted with aqueous NaCO solution. The benzene layer was dried over MgSO and filtered. Thefiltrate was'reduced in vacuo to a syrup. The LR. spectrum of the syrupshowed strong amide absorption at 1640 cm. The hydrochloride salt of thedesired product was obtained by utilization of the procedure describedfor salt formation in the above. Yield 9.7 g., M.P. 199202 C.

Analysis.Calcd. for C H N ClO (percent): N(Dumas) 7.02; C, 72.25; H,7.83. Found (percent): N(Dumas) 6.89; C, 71.50; H, 7.96.

EXAMPLE l2 N-(3-methylphenyl)-N-(1,3,4,6,7,1lb-hexahydro-ZH- benzo [a]quinolizine-Z-yl propionamide (A)2-(m-methylanilino)-1,3,4,6,7,11b-hexahydro-2H- benzo[a]quinolizine.-Asolution of 1,3,4,6,7,11b-hexahydro-2H-benzo[aJquinolizine-Z-one (20.1g.; 0.1 M), mtoluidine (10.7 g.; 0.1 M), and a catalytic amount ofptoluenesulfonic acid in 300 m1. of benzene was refluxed under anitrogen atmosphere for 17 hours. A Dean-Stark trap was utilized toremove 1.8 ml. of H 0. The solvent was removed from the reactionsolution in vacuo to yield a dark orange oil. The IR. spectrum exhibitedstrong imine absorption. The oil was dissolved in 250 ml. of MeOH andcooled in an ice bath. Solid NaBH, (8 g.) was added portionwise, withstirring, to the cold MeOH solution. After bubbling ceased, the solutionwas refluxed for 3 hours and cooled. The solvent was removed in vacuoand the resulting semi-solid residue was extracted with CHCl vs. H O.The CHCI extracts were dried over MgSO then filtered. The filtrate wasreduced in vacuo to an oil. The LR. spectrum did not exhibit any imineor ketone absorptions. The oil was dissolved in hot aqueous EtOH andupon cooling a white crystalline product formed. The solid was removedby filtration, washed with cold aqueous EtOH, and dried overnight invacuo at 78 C.

(B) N-(3-methyl-phenyl) N (1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine 2 yl)propionamide hydrochloride-A solution of1,3,4,6,7,llb-hexahydro-Z-(mmethylanilino) 2H benzo [a] quinolizine (5.1g.; 0.0174 M) and propionic anhydride (2.6 g.; 0.02 M) in 100 ml. ofbenzene was refluxed for 24 hours. The solvent was removed in vacuo and100 m1. of H added to the resulting residue. The mixture was heated on asteam bath and concentrated HCl added to eflect dissolution. The hotsolution was rendered alkaline with K CO and cooled. The mixture wasextracted with Et O, the combined Et O extracts dried over MgSO, andfiltered. Removal of the solvent in vacuo from the filtrate yielded ayellow oil which crystallized upon setting. The yellow solid wasrecrystallized from n-heptane. Yield 4.0 g., M.P. 126 127 C.

Analysis.Calcd. for C H N O (percent): N, 8.04; C, 79.27; H, 8.10. Found(percent): N, 7.90; C, 79.87; H, 8.21.

The solid was dissolved in 2-propanol and 2.7 N HCl in 2-propanol ml.)added. Anhydrous Et O was added to the solution until it became cloudy.An oil formed which did not crystallize. The solvent was removed invacuo to yield a light yellow oil. The oil was dissolved in EtOH andconcentrated on a hot plate by bolling. EtOAc was added to the solutionand a clear oil formed which crystallized after setting for one week.The white solid was removed by filtration. Yield 3.5 g., M.P. 192- 198C.

Analysis.-Calcd. for C H N OCl (percent): N, 7.28; C, 71.75; H, 7.59.Found (percent): N, 7.21; C, 71.17; H, 7.67.

EXAMPLE 13 N-( 1,3,4,6,7,1 1b-hexahydro-2H-benzo[a] quinolizine-Z-yl)-2',4'-dimethoxypropionanilide hydrochloride (A) 2 (2,4dimethoxyanilino) 1,3,4,6,7,11b hexahydro 2H benzo[a]quinolizine.-Asolution of 1,3,4,6,7,11b hexahydro 2H benzo[a] quinolizine 2- one (40.2g.; 0.2 M), 2,4-dimethoxyaniline (33.7 g.; 0.22 M), and a catalyticamount of p-toluenesulfonic acid in 500 ml. of benzene was refluxed forhours in an atmosphere of nitrogen using a Dean-Stark trap to remove HO. The reaction solution was cooled and the solvent removed in vacuo toyield a dark syrup. The LR. spectrum showed imine absorption at 1660 cmfThe syrup was dissolved in 500 ml. of MeOH and cooled in an ice-bath.Solid NaBH (16.0 g.) was added portionwise with stirring to the abovecold solution. After bubbling had ceased, the mixture was refluxed forone hour and cooled. The solid which formed was removed by filtration,washed with cold MeOH, and air dried at room temperature. Yield 36.8 g.,M.P. 116l18 C.

Analysis.-Calcd. for C H N O (percent): N- (Dumas) 8.28; C, 74.53; H,7.74. Found (percent): N(Dumas) 8.11; C, 74.21; H, 7.88.

(B) N (1,3,4,6,7,11b hexahydro 2H benzo[a] quinolizine 2 yl) 2',4'dimethoxypropionanilide hydrochloride.--A solution of 2 (2,4dimethoxyanilino) 1,3,4,6,7,11b hexahydro 2H benzo [a]quinolizine (16.9g., 0.05 M) and propionic anhydride (13.0 g.; 0.1 M) in 200 ml. ofbenzene was refluxed for 72 hours, cooled and extracted with an aqueoussolution of Na CO The benzene solution was then dried over MgSO andfiltered. The filtrate was reduced in vacuo to an oil. The IR. spectrumshowed strong anhydride absorptions in addition to the strong amideabsorption at 1640 cmr The oil was dissolved in 500 ml. of anhydrous EtO and gaseous HCl was bubbled through the cooled, stirred solution. Awhite solid formed which was removed by filtration and washed well withanhydrous Et O. The solid was recrystallized, first from 2-propanol,then from Me0H/Et O. Yield 16.6 g., M.P. 265-267 C.

Analysis.Calcd. for C H N O Cl (percent): N- (Dumas) 6.50; C, 66.88; H,7.25. Found (percent): N(Dumas) 6.40; C, 66.68; H, 7.45. i

EXAMPLE 14 N-( 1,3,4,6,7,1 lb-hexahydro-ZH-benzo [a] quinoliziue-2-yl)3',4,5'-trimethoxypropionanilide hydrochloride (A) 1,3,4,6,7,11bhexahydro 2 (3,4,5 trimethoxyanilino) 2H benzo[a]quinolizine.-A solutionof 1,3,4,6,7,11b hexahydro 2H benzo[a]quinolizine 2- one (30.2 g.; 0.15M), 3,4,5-trimethoxyaniline (27.5 g.; 0.15 M), and a catalytic amount ofp-toluenesulfonic acid in 500 ml. of benzene was refluxed for 16 hoursin an atmosphere of nitrogen using a Dean-Stark trap to remove H O. Thesolution was cooled and the solvent removed in vacuo to yield a darkreddish-orange syrup. The I.R. spectrum showed strong imine absorptionat 1660 cm.- The syrup was dissolved in 400 ml. of MeOH and theresulting solution cooled in an ice-bath. Solid NaBHL, (12 g.) was addedportionwise, with stirring, to the above cold solution. When bubblinghad ceased the solution was refiuxed for 4 hours and cooled to roomtemperature. The solvent was removed in vacuo and the residue was shakenwith 600 ml. of a mixture of H 0 and Et O (50:50). The resulting twophases were separated and the aqueous phase extracted with Et O. Theextracts were dried over MgSO and filtered. The filtrate was reduced invacuo to a dark syrup. The dark syrup was dissolved in 600 ml. ofbenzene and divided into two equal 300 ml. aliquots.

(B) N (1,3,4,6,7,11b hexahydro 2H benzo[a] quinolizine 2 yl) 3',4',5'trimethoxypropionanilide hydrochloride-1,3,4,6,7,11b hexahydro 2 (3,4,5-trimethoxyanilino) 2H benzo[a]quinolizine, the 300 ml. portion from (A),was added to propionic anhydride (19.5 g.; 0.15 M). The resultingsolution was refluxed for 24 hours and cooled to room temperature. Thesolvent was removed in vacuo to yield a dark syrup. The syrup wasdissolved in 100 ml. of anhydrous Et O and 37.5 ml. of 2.06 N HCl in2-propano1 was added with stirring. Additional anhydrous Et O was addeduntil a product precipitated. The solid was separated by filtration andwashed with anhydrous Et O. The solid was recrystallized three timesfrom 2-propanol/Et O. Yield 8.1 g., M.P. 197.5-198 C.

Analysis.Calcd. for C H N O Cl (percent): N- (Dumas 6.08; C, 65.14; H,7.22. Found (percent): N(Dumas) 5.89; C, 64.72; H, 7.36.

EXAMPLE 15 N- (4-cyanophenyl -N-( 1,3,4,6,7,1lb-hexahydro-ZH- benzo [a]quinolizine-Z-yl propionamide (A) 2(p cyanoanilino) 1,3,4,6,7,11bhexahydro- 2H benzo[a]quinolizine-A solution of 1,3,4,6,7,11bhexahydro2H benzo[a]quinolizine 2 one (20.1 g.; 0.1 M), p-aminobenzonitrile (11.8g.; 0.1 M), and a catalytic amount of p-toluenesulfonic acid in 250 ml.of benzene was refluxed under a nitrogen atmosphere for 96 hours. ADean-Stark trap was utilized to remove 1.2 ml. of H 0 (theory=1.8 ml. HO). The volume was reduced to ml. by distillation. The orange solidformed upon cooling was removed by filtration. The LR. spectrumexhibited strong nitrile absorption at 2225 cm. and strong imineabsorption at 1670 cm.- There was no ketone absorption. The orange solidwas suspended in 300 m1. of MeOH and cooled in an ice-bath. Solid NaBH,(20 g.) was added portionwise with stirring. When bubbling had ceased,the resulting solution was refluxed for 2 hours, cooled and the solventremoved in vacuo. The resulting semi-solid residue was extracted withCHC13 vs. H O. The CHCl extracts were dried over MgSO and filtered. Thefiltrate was reduced in vacuo and the LR. spectrum of the resultingyellow oil did not exhibit any imine absorption but retained the desirednitrile absorption. A light yellow solid was obtained from the yellowoil I by dissolution of the oil in. hot aqueous EtOH andallowing'theresulting solution to cool.

(B) N-(4-cyanophenyl) N (1,3,4,6,7,11b-hexahydro- 2Hbenzo[a]quinolizine-Z-yl)propionamide hydrochloride.-A solution of 2-(pcyanoanilino) 1,3,4,6,7,11bhexahydro-2H-benzo[a]quinolizine (5.3 g.;0.0175 M) and propionic anhydride (2.6 g.; 0.02 M) in 100 ml. of benzenewas refluxed for 24 hours. The solvent was removed in vacuo and theresulting residue stirred in 100 ml. of hot H O to which 10 ml. ofconcentrated HCl was added to effect dissolution. The resulting solutionwas rendered basic with K CO The mixture was extracted with OHCl and thecombined CHCl extracts were dried over MgSO and filtered. Removal of thesolvent in vacuo from the filtrate yielded an oil which was shown by LR.to be the starting amine. Propionic anhydride v(50 ml.) was added to theoil and the resulting mixture was heated on a steam bath for 48 hours.The solution was cooled and 100 m1. of H added followed by an additionof 2 5 ml. of concentrated HCl. The solution was rendered alkaline withNaOH and extracted with CHCl The com bined CHC1 extracts were dried overMgSO filtered and the solvent removed from the filtrate in vacuo. Theresulting solid residue was recrystallized from benzene and n-heptane.Yield 3.5 g., M.P. 105-185 C.

Analysis.Calcd. for C H N O (percent): N, 11.68; C, 76.85; H, 7.01.Found (percent): N, 11.77; C, 76.20; H, 7.00.

The solid was dissolved in hot 2-propanol and two successive 10 ml.portions of 2.7 N [HCl in 2-propanol were added. The solution wasconcentrated by boiling on a hot plate and EtOAc was added untilcrystals began to form. Upon cooling, a white solid formed which wasremoved by filtration. Yield 1.4 g., M.P. 248258 C. dec.

Analysis.Calcd. for C H N OCl (percent): N, 10.61; C, 69.78; H, 6.62.Found (percent): N, 10.10; C, 69.62; H, 6.73.

EXAMPLE 16 N-(4-biphenyl)-N-( 1,3 ,4,6,7,1 lb-hexahydro-ZH-benzo- [a]quinolizine-2-yl propionamide hydrochloride (A) 2-(4 -biphenylamino)l,3,4,6,7,11b-hexahydro- 2H-benzo[a]quinolizine.-A solution of1,3,4,6,7,1lbhexahydrO-ZH-benzo[a]quinolizine-2-one (20.1 g.; 0.1 M),4-aminobiphenyl (16.9 g.; 0.1 M), and a catalytic amount ofp-toluenesulfonic acid in 250 ml. of benzene was refluxed under anitrogen atmosphere for 18 hours. A Dean-Stark trap was utilized toremove 1.8 ml. of H 0. The solvent was removed in vacuo and the IR.spectrum of the resulting reddish-orange oil exhibited strong absorptionfor imine at 1670 CHIP-1. The oil was dissolved in 500 ml. of MeOH andthe resulting solution cooled in an ice-bath. Solid NaBH, (8 g.) wasadded portionwise with stirring. When bubbling ceased, the solution wasrefluxed for 2 hours. A solid began to precipitate from the solution andapproximately 350 ml. of solvent was removed by distillation. Aftercooling, the mixture was filtered to yield a light colored solid. Thesolid was recrystallized from 95% EtOH.

(B) N (4 -biphenyl) N (l,3,4,6,7,1lb-hexahydro- 2H-benzo[a]quinolizine 2yl)propionamide hydrochloride.A solution of2-(4-biphenylami11o)-1,3,4,6,7,11bhexahydro-2H-benzo[a]quinolizine (8.9g.; 0.0251 M) and propionic anhydride (3.9 g.; 0.03 M) in 100 m1. ofbenzene was refluxed overnight. The solvent was removed in vacuo and theresulting residue stirred in 100 ml. of hot H O. Concentrated HCl (10ml.) was added to effect dissolution and the resulting hot solution wasrendered alkaline with K CO An oil formed which immediately solidifiedin the hot solution. The resulting mixture was cooled, the solid removedby filtration and washed with H O to yield a brown solid (11 g.) whichslowly melted above 115 C. The I.R. spectrum was devoid of N-Habsorption but exhibited both. strong amide absorption at 1645 (31117and salt-like absorption around 2500 emf- The brown solid was dissolvedin hot ClHCl and filtered 12 through charcoal. The filtrate was boiledon a hot plate and successive portions of EtOAc added as the CHCl wasremoved until a solid began to crystallize in the hot solution. Themixture was cooled and the resulting solid removed by filtration toyield 4.0 g., M.P. 265-275 C. dec. The solid was dissolved in boiling HO to which 10 ml. of concentrated HCl had been added. The hot solutionwas filtered through charcoal to yield a colorless solution. Uponcooling, a white solid formed which was removed by filtration to yield2.2 g. of a white solid which softened at 165 C. and melted withdecomposition at 265-275 C.

The white solid was dissolved in MeOH and the resulting solution wasboiled to remove H O at an azeotrope. The solution was then concentratedfurther by boiling and EtOAc was added. Upon cooling a white solidformed which was removed by filtration. Yield 2.0 g., M.P. 274- 279 C.dec.

Analysis.-Calcd. for C H N OCl (percent): N, 6.27; C, 75.24; H, 6.99.Found (percent): N, 6.17; C, 75.74; H, 7.28.

EXAMPLE 17 N-( 1,3 ,4,6,7, 1 lb-hexahydro-ZrH-benzo [a] quinolizine-2-yl) propionamide hydrochloride (A) 1,3,4,6,7,11b hexahydro 2Hbenzo[a]quinolizine-2-one oxime.l,3,4,6,7 ,1 lb-hexahydro 2H benzo-[aJquinolizine-2-one (20.1 g.; 0.1 M), hydroxylamine hydrochloride (20.1g.; 0.289 M), ml. of pyridine and 100 ml. of anhydrous EtOH was refluxedfor 2 /2 hours. The solvent was removed in vacuo, the solid residuetriturated with 100 ml. of cold H 0 and filtered. The solid wasdissolved in 1.5 l. of hot H O then cooled in an icebath. The coldsolution was rendered alkaline with NaHCO and the resulting precipitateremoved by filtration.

(B) 2 amino 1,3,4,6,7,1lb-hexahydro-2H-benzo[a] quin0liZine.A solutionof 1,3,4,6,7,llb-hexahydro-ZH- benzo[a]quinolizine oxime (15.0 g.;0.0693 M) in 275 ml. of dry THF was added dropwise, with stirring, to asuspension of LiAlH (7.8 g.; 0.2079 M) in 300 ml. of dry THF. Theresulting mixture was refluxed for 24 hours. The reduction complex andexcess LiAlH were decomposed by the successive dropwise addition of 7.8ml. of H 0 in 78 ml. of THF, 5.85 ml. of 20% NaOH, and 27.3 ml. of H 0to the ice-cold, stirred mixture. The mixture was stirred in theice-bath for 2 hours, filtered and wa sHe d with THF. The filtrate wasreduced in vacuo to an oil which was dissolved in CHCl dried over MgSOand filtered. The filtrate was reduced in vacuo to a yellow oil.

(C) N (1,3,4,6,7,1lb hexahydro 2H-benzo[a]quinolizine-Z-yl)-propionamide hydrochloride.A solution of 2 amino1,3,4,6,7,llb-hexahydro-2H-benzo[a] quinolizine (7.0 g.; 0.0346 M) (theoil from (B) and propionic anhydride (4.5 g.; 0.0346 M) in 200 ml. ofbenzene was refluxed for 7 /2 hours. The solvent was removed in vacuoand the resulting oil was stirred with hot H O as concentrated Hcl wasadded to eflect dissolution. The solution was rendered alkaline with 20%NaOH. The mixture was extracted with CHCl The combined CHCl extractswere dried over MgSO, and filtered. The solvent was removed in vacuofrom the filtrate and the residue was crystallized from a mixture ofbenzene and n-heptane. The solid was dissolved in 65 ml. of hot2-propanol. After cooling the solution, 10 m1. of 2.7 N HCl in 2-propanol was added. The solution was concentrated by boiling and EtOAcwas added. After the solution had been cooled to 5 C. a small amount ofanhydrous Et O was added and the solution was left at 5 C. for 4 days. Asolid formed which was removed by filtration. Yield 3.5 g. which slowlydecomposes at 200-230 C. I Analysis.Calcd. for C H N OCl (percent): N,9.51; C, 65.19; H, 7.87. Found (percent): N, 9.41; C, 64.55; H, 8.00.

13 What is claimed is: 1. A compound selected from the group consistingof compounds of the formula:

in which R isa member selected from the group consisting of H, OH andlower alkoxy, R is a member selected from the group consisting of H, OHand lower alkoxy, R is a member selected from the group consisting of H,(lower) alkyl, cycloallgyl of between 3 and 7 carbon atoms, phenyl,substituted phenyl, diphenyl, phenyl(lower)alkyl and substitutedphenyl(lwer)alkyl in which the substituents are homogeneous membersselected from the group consisting of halogen; methyl, ethyl[(lowefialkyl], methoxy, ethoxy, mono cyano, methoxy or ethgxy carbonyland m 6. The compound of claim 1 which is N-phenyl-N- (1,3,4,6,7,11bhexahydro 2H benzo[a] quinolizine-Z- yl) acetamide;

7. The compound of claim 1 which is N-phenyl-N- (1,3,4;6,7,11bfhexahdyro 9,10 dimethoxy-2H-benzo- [a]quino1izine-2-yl)propionamide.

8. The compound of claim 1 which is N-phenyl-N- (1,3,4,6,7,11b,;-hexahydro 2H benzo[a]quinolizine-2- yl)cy :loprop'2 ne carboxamide.

9. The compound of claim 1 which is N-phenyl-N-(1,3,4,6,7,11l;ihexahydro 2H benzo[a]quinolizine- 2-yl)benzoani i ide.

10. The ccif" pound of claim 1 which is N-cyclohexyl- N-(1,3,4,6,7,1f1bhexahydro 2H benzo[a] quinolizine- 2-yl)propionalr "nide.

11. The c 'mpound of claim 1 which is N-benzyl-N- (1,3,4,6,7,11bhexahydro 2H-benzo[a]quinolizine-2- yl)propionarrti ;ie.

12. The compound of claim 1 which is N-phenethyl- N-[2-(1,3,4,6,7,l1bhexahydro 2H benzo[a]quinolizine-2-yl) ]propionamide.

13. The compound of claim 1 which is N-(3-methylphenyl) N a(1,3,4,6,7,11b hexahydro-2H-benzo[a]- quinolizine-2-yl propionamide.

14. The compound of claim 1 which is N-(1,3,4,6,7, 11b hexahydro 2Hbenzo[a]quinolizine-2-yl)-2',4- dimethoxypropionanilide.

15. The compound of claim 1 which is N-(1,3,4,6,7, 11b hexahydro 2Hbenzo[a]quinoliZine-2-yl)-3',4', 5'-trimethoxypropionanilide. Y

16. The compound of claim 1 which is N-(4-cyanophenyl) N @i(1,3,4,6,7,11b hexahydro-2H-benzo[a] quinolizine-Z-yl)propionamide.

17. The conipound of claim 1 which is N-(4-biphenyl)- N (l,3,4,6,7;, l1bhexahydro-2Hbenzo[a]quinolizine- 2-yl propionamide.

18. The compound of claim 1 which is N (1,3,4,6,7, 11b hexahydroZH-benzo[a]quinolizine-Z-yl)propionamide. 1

References Cited UNITED STATES PATENTS 9/1962 Mull 260 -287 1-/1969 Bell260-288 DONALD G. DAUS, Primary Examiner

